Substituted cyclohexene carboxylic acids and derivatives thereof

ABSTRACT

NOVEL SUBSTITUTED CYCLOHEXENE CARBOXYLIC ACIDS AND DERIVATIVES THEREOF USEFUL AS ANTI-FERTILITY AGENTS.

United States Patent Office 3,706,784 Patented Dec. 19, 1972 ABSTRACT OF THE DISCLOSURE Novel substituted cyclohexene carboxylic acids and derivatives thereof useful as anti-fertility agents.

This invention relates to novel substituted cyclohexene carboxylic acids and derivatives thereof. More particularly, the present invention relates to cyclohexane carboxylic acids and derivatives thereof of the following formula:

wherein R is chloro, fiuoro, hydroxy and the hydrolyzable carboxylic esters thereof, lower alkoxy, hydroxymethyl and the hydrolyzable carboxylic esters thereof, formyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifiuoromethyl, cyano, phenyl, benzyl, or

the group COOR in which R is hydrogen, an alkali metal or lower alkyl;

R is methyl or ethyl;

R is hydrogen, methyl, ethyl or isopropyl;

R is hydrogen, hydroxy and the hydrolyzable carboxylic esters thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2'-yloxy, tetrahydrofuran-2'-yloxy the group OSO OX or the group OPO(OX) in which X is hydrogen or an alkali metal;

R is a lower alkyl, hydrogen, hydroxy and the hydrolyzable carboxylic esters thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2-yloxy, tetrahydrofuran-2'-yloxy, the group OSO OX or the group OPO(OX) in which X is hydrogen or an alkali metal;

R is hydroxymethyl and the hydrolyzable carboxylic esters thereof, formyl, COCl, COF, CONH or the group COOR in which R is hydrogen, an alkali metal or lower alkyl; and each of Z and Z is a carbon to carbon single bond or double bond, provided that at least one of Z and Z' is a single bond that when R is either COCl or COF that R and R are other than the group OSO OX or the group OPO(OX) The term lower alkyl, as used herein, refers to a straight or branched saturated aliphatic hydrocarbon group of from one to about six carbon atoms. The term lower alkoxy, as used herein, refers to the group OAlkyl in which alkyl is a lower alkyl group as defined herein. The wavy lines (i) at the 2-position indicates alpha and/or beta configuration, i.e. the cis and trans isomers.

The term hydrolyzable carboxylic esters, as used herein, refers to those hydrolyzable carboxylic ester groups conventionally employed in the synthetic hormone art derived from hydrocarbon carboxylic acids. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from 1 to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate. trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-p,p-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fl-chloropropionate, trichloroacetate, p-chlorobutyrate, and the like.

The compounds of Formula A above are produced according to the following outlined process:

R1 0 R5 (VI) 1 o no 9 E R1 R 3 B) 1 R1 R! R6 /\---COOH I u ---coon out-R ---CHrR n E R4 R3 R 3 VII (VIII) In the above formulas, R R and R have the same meaning as given hereinabove, R is hydrogen, fluoro, chloro, hydroxy and carboxylic esters thereof, lower alkoxy, cyano, trichloromethyl, trifluoromethyl, phenyl, benzyl or the group -COOR' in which R is hydrogen or lower alkyl and R is hydrogen or methyl.

In the practice of the above outlined process, a compound of Formula I is reacted with a tetronic acid of Formula II in an aqueous solution of a water-miscible organic solvent such as methanol, ethanol, monoglyme, digylme, tetrahydrofuran, and the like at about room temperature to about 75 C. for from about 1 to 40 hours to afford the a-substituted tetronic acid (HI). In this reaction, temperatures above room temperature are preferred when the phenyl ring of the isothiouronium acetate (I) bears a free hydroxy group or is unsubstituted. This reaction, although not necessary, can be carried out in the presence of an alkaline catalyst, e.g. organic tertiary amines such as triethylamine or inorganic alkalines such as sodium or potassium hydroxide. The reaction is generally complete in about one to four hours. A compound of Formula III is then contacted with an acid, preferably a strong acid, either alone or in organic solvent inert to the reaction such as benzene, xylene, methanol, dioxane, and the like at a temperature of from about room temperature to the reflux temperature of the solvent for a period of about 1 to 24 hours to form an enol lactone of Formula IV. Exemplary of the inorganic and organic acids suitable for this reaction are p-toluenesulfonic acid, sulfosalicyclic acid, anhydrous orthophosphoric acid, sulfuric acid, formic acid, hydrochloric acid, and the like. Preferably, this ring cyclization is effected by treatment with p-toluenesulfonic acid in benzene, xylene, or toluene at reflux for about four hours. When the phenyl ring of III is unsubstituted or bears a free hydroxy group, the solvent is preferably xylene or toluene.

An enol lactone of Formula IV is then treated with an aqueous water-miscible organic solvent solution of a base such as the alkali metal hydroxides, and the like at about room temperature for a period of about one to several hours followed by acidification of the reaction mixture to afford an equilibrium mixture of a tautomeric cis keto acid of Formula V-A and cis lactol of Formula V-B. This equilibrium mixture is predominantly the cis lactol and for the sake of clarity and to avoid undue prolixity hereinafter, reference to the cis lactol is understood to be inclusive of the cis keto acid, i.e. the equilibrium mixture.

A cis lactol is then subjected to carbonyl reduction to afford a cis acid of Formula VI. Alternatively, the cis lactol can be first converted into the corresponding cis keto ester (VI') by treatment with a lower alkyl halide, preferably an alkyl bromide or iodide containing up to six carbon atoms in an organic solvent such as dimethylacetamide or dimethylformamide at about room temperature for from about 1 to about hours and thereafter subjecting the cis keto ester to carbonyl reduction to give the acid ester (V-I) which is converted into the free acid (VI) by alkaline hydrolysis. Although the description following is specific to carbonyl reduction of the cis lactol as outlined above, it is equally applicable or useful for carbonyl reduction of the keto ester (VI').

---CO0Alkyl --COOAlkyl TR RI ..I 2 4311 -32 H (l H R R (VI') (VI) The cis lactol (V-A and V-B) is subjected to carbonyl reduction to afford the cis acid (VI). Carbonyl reduction can be accomplished electrolytically in a divided electrolysis cell. In carrying out carbonyl reduction by the electrochemical method, reduction is effected at the cathode of a divided electrolysis cell in an electrolytic medium comprising mineral acid electrolyte, water and a water-miscible inert organic solvent at a current density of about 0.01 to about 0.2 amps/cm. and at a temperature of from about 0 C. to about 70 C., for a period of about 1 to about 16 hours. Mineral acids suitable for the electrolytic medium are sulfuric acid, hydrochloric acid, perchloric acid, hydrobromic acid, phosphoric acid, and the like. Preferably, sulfuric acid or perchloric acid. Water-miscible organic solvents inert to the electrolysis reaction suitable for the electrolytic medium are ethers such as dioxane, tetrahydrofuran, and the like; lower monohydric alcohols such as methanol, ethanol, and the like; lower alkylene glycols such as ethylene glycol, propylene glycol, and the like; mixtures of the foregoing solvents, and the like in which the cis lactol is soluble or substantially soluble.

The amount of solvent present in the electrolytic medium can range from the amount which is sufficient to dissolve or substantially dissolve the cis lactol up to about 94%, preferably from about 20% to about 85%, by weight, of the total electrolytic medium. The amount of acid in the medium can range from about 1% to about 20%, by weight, of the total electrolytic medium, preferably from about 2% to about 15%. The amount of water in the medium should be at least 5%, by weight, of the total electrolytic medium, preferably from about 10% to about 7.5%. A preferred medium is an equal volume of the inert organic solvent and an equal volume of 10% to 30% aqueous sulfuric acid, by weight.

Cathode materials useful in the process of the electrochemical reduction include the high hydrogen over-voltage materials such as lead, cadmium, mercury, and the like. The cathode may be in any number of physical forms but preferably in a form having a high surface such as a sheet or a wire mesh which is sufiiciently rigid to be used as a stirring means. Anode materials useful for this reduction are difiiculty oxidizable conductors such as carbon, platinum, iron, lead, and the like. In general, the anode material may be any conductor which is not attacked by the electrolytic medium in a manner which would transform it into a soluble state over a short period.

A current density of about 0.01 to about 0.2 amps./ cmf preferably from about 0.02 to about 0.1 can be used. Depending primarily upon the current efficiency of the system, reduction times of about 1 to about 16 hours are generally employed. A temperature within the range of about 5 C. to about 40 C. is preferred.

A cyclohex-3-ene-l-carboxylic acid (VI) can be reduced to afford the corresponding 3,4-dihydro compound (VIII). This reduction can be accomplished catalytically using, for example, a palladium catalyst such as palladium-on-charcoal, and the like.

A cyclohex-4-ene-l-carboxylic acid (VII) can be obtained by treatment of a cyclohex-3-ene-l-carboxylic acid (VI) with hydrogen chloride, and the like in an organic solvent such as benzene, toluene, and the like according to the procedure of Hogg and Nathan, US. Patent 2,582,253.

A process which is especially useful for the preparation of the trans isomers of Formula V' is to treat an enol lactone (IV) with an aqueous water-miscible organic solvent solution of an alkali metal hydroxide, e.g. sodium or potassium hydroxide, at about room temperature for a period of several hours or at higher temperatures, e.g. reflux, for a shorter period of time to afford a trans keto acid of Formula V together with a minor amount of an equilibrium mixture of the cis isomers (V-A and V-B).

ll 1H0 s The keto acid (V') is subjected to the electrochemical reduction procedure described above to afford the corresponding acid.

In carrying out the opening of the enol lactone (IV) by treatment with alkali hydroxide, reaction times of the order of about one to three hours furnish predominantly the cis isomer whereas reaction times extending beyond about three hours lead to formation of the trans isomer. In other words, formation of the trans isomer is increasingly promoted as the reaction time extends beyond about three hours.

'In practicing the above outlined process, acid labile groups in a compound of Formulas III and V, such as tetrahydropyran-2'-yloxy or tetrahydrofuran-2'-yloxy, are generally hydrolyzed in the course of the reaction to free hydroxy groups. The free hydroxy group(s) is re-etherified subsequently, if desired, by treatment with dihydropyran or dihydrofuran and an acid catalyst such as ptoluenesulfonic acid either alone or in a cosolvent such as benzene. Also, base labile groups in a compound of Formula IV, such as an acyloxy group, are generally hydrolyzed in the course of the reaction to free hydroxy groups which can be re-esterified subsequently, if desired, using conventional esterification procedures.

The compounds of the present invention of Formula A wherein R is hydroxymethyl can be prepared by treating a compound of Formula III wherein R is hydrogen with formaldehyde and sodium methoxide in the presence of sodium hydroxide in aqueous dioxane and thereafter subjecting the thus-prepared lat-hydroxymethyl substituted tricyclic compound to the process steps described above for the preparation of the acid (VI or VI). Alternatively, the hydroxymethyl group can be introduced at a later stage in the process. For example, subjecting a compound of Formula VI or VI wherein R is hydrogen to the above treatment with formaldehyde and sodium methoxide to obtain the corresponding 2-hydroxymethyl substituted compound.

The novel compounds of Formula A wherein R is fluoromethyl or chloromethyl can be obtained by treatment of a hydroxymethyl substituted compound of Formula IH ('IH, R is hydroxymethyl) with N-(2-chloro-l,l,2- trifiuoromethyl)diethylamine and thionyl chloride, respectively, and thereafter subjecting the thus-prepared a-fluoromethyl and rat-chloromethyl cyclic compound to the process steps described above for the preparation of the acid (VI or VI). Alternatively, a halomethyl group can be introduced at a later stage in the process by treatment of the corresponding hydroxymethyl substituted compound.

The novel compounds of Formula A wherein R is formyl can be obtained by treating a hydroxymethyl substituted compound with N,N'-dicyclohexylcarbodiimide 1n dimethyl sulfoxide in the presence of acid or with chromic oxide in pyridine. The conversion of a hydroxymethyl group to a formyl group is preferably accomplished using a 2-hydroxymethyl substituted compound of Formula VI or VI".

The Z-difiuoromethyl and 2-dichloromethyl compounds of the present invention (A, R is difluoromethyl or dichloromethyl) are obtainedby treating a formyl substituted compound with sulfur tetrafluoride and phosphorus pentachloride, respectively. This conversion can be accomplished at any stage of the process but is preferably accomplished using a formyl substituted compound of Formula IV (IV, R is formyl) and thereafter subjecting the thus-obtained difluoromethyl compound or dichloromethyl compound to the above described procedures.

The compounds of the present invention of Formula A above wherein R is hydroxymethyl and the hydrolyzable carboxylic esters thereof, formyl, COCl, COF, CONH or the group COOR in which R is lower alkyl or an alkali metal are obtained according to the following procedures.

The acid chlorides are obtained by treating the free acid with triphenyl phosphine in carbon tetrachloride or by treatment with thionyl chloride or oxalyl chloride in an inert halogenated solvent such as chloroform or methylene chloride at about room temperature for from about 1 to 12 hours. Acid labile groups may be cleaved during this reaction and consequently, if a compound of Formula A wherein R and R or both are tetrahydropyran-2'-yloxy or tetrahydrofuran-2'-yloxy is desired, it is necessary to etherify the free hydroxy compound using, e.g. the etherification procedure described hereinabove.

The compounds of Formula A wherein R is are obtained by treating the free acid with N-(Z-chloro- 1,1,2-trifiuoroethyl)diethylamine in an inert solvent such as ether, acetonitrile or methylene chloride at a temperature of about 0 C. to about reflux for l to 10 hours.

The compounds of Formula A wherein R is H -CNH2 are obtained by treating the free acid with thionyl chloride in benzene at about reflux followed by treatment with anhydrous ammonia at about room temperature.

The compounds of Formula A wherein R is the group i C-OR in which R is an alkali metal, can be obtained by treating the free acid with a dilute alkali metal hydroxide solution or a dilute alkali metal bicarbonate solution in a lower alcohol solvent, e.g. ethanol, at about room temperature. The alkali metal salt can then be converted into the acid ester (A, R is I? O-OR in which R is lower alkyl) by treatment with a lower alkyl iodide or bromide in dimethylacetamide or dimethylformamide at about room temperature.

The compounds of Formula A in which R is hydroxymethyl are prepared by treating the ester (A, R is it C-OR in which R is lower alkyl) with, for example, lithium aluminum t-butoxide in an inert solvent such as tetrahydrofuran. The hydroxymethyl compound can be subjected to conventional esterification procedures to obtain the corresponding hydrolyzable carboxylic esters or alternatively they can be converted into the corresponding aldehyde (A, R is formyl) by treatment with, e.g. chromium trioxide in pyridine.

The compounds of the present invention having the group OPO('OX) can be prepared from the corresponding free hydroxy substituted compound by treatment with, e.g. B-cyanoethyl phosphate and a condensing agent followed by hydrolysis of the reaction product or a functional derivative of phosphoric acid such as dibenzylphosphate halide followed by catalytic hydrogenolysis. The phosphoric acid ester can be transformed into the corresponding alkali metal salts by treatment with base, e.g. sodium ethylate, sodium or potassium bicarbonate, and the like. By controlling the amount of base both the mono and di salts can be obtained. Suitable procedures are described in, e.g. U.S. Pats. 2,936,313, 3,248,408, 3,254,100, 3,257,385, 3,268,562 and 3,345,259 and Chem. & Ind., pp. 1174- (July 8, 1967).

The compounds of the present invention having the group OSO OX can be prepared from the corresponding free hydroxy compound by treatment with, e.g. sulfur trioxide-pyridine complex at low temperatures. See, for example, British Pat. 926,472 (1963), I. Am. Chem. Soc., 63, 1259 (1941), J. Biol. Chem., 115, 381 (1936), and Steroids, 10, No. 3, 310 (Sept., 1967).

The cyclohexene carboxylic acids and cyclohexane carboxylic acids of formula A above are excellent anti-fertility agents. They can be used and administered in the same manner as the known cyclohexene carboxylic acids, see for example, U.S. Pats. 2,582,253 and 3,344,147. The compounds of Formula A above by reason of their excellent anti-fertility activity are useful in the control of pests, for example rodents such as rats, mice, nutria, and the like. For this purpose, the compounds are admixed with a suitable bait such as grain, salmon, and the like placed in an area accessible to the rodents. The amount of anti-fertility agent incorporated into the bait is not critical so long as it does not exceed the limit above which the rodent can detect the presence of the agent. The anti-fertility agent/bait mixture is preferably made available to the pest on, for example, alternate days in an amount which, by past experience, can be expected to be entirely consumed in two days.

Edible carriers suitable as a bait include liquids, solids and mixtures thereof such as water, milk, molasses, corn oil, peanut oil, cottonseed oil, sugar, peanut butter, chicken mash, dairy mixes, corn, oats, wheat, bran, meat, fish, lard, chopped grass or hay, cheese, salt, and the like. In addition, conventional pest attractants and other additives normally employed in baits can be added. The compositions of the antifertility agent and bait can be prepared, for example, as a granular mix, as a paste, as a syrup, in the form of pellets for ease of application, and the like. Other forms of carriers can also be used such as forming a solution, e.g. a salt solution or mixture containing a small amount of the anti-fertility agent, and impregnating a suitable carrier such as cellulosic materials, e. g. wood, with the solution.

Tetronic acid and substituted tetronic acid characterized by Formula II can be prepared by conventional procedures known in the art. For example, a-bromo- -alkyl tetronic acids can be prepared by bromination of a 'y-alkyl tetronic acid in chloroform as described in Briegleb and Strohmeier, Angew. Chem., 64, 409 (1952). In an analagous manner, chlorination of a 'y-alkyl tetronic acid in chloroform affords the corresponding a-chloro-y-alkyl tetronic acids. Alternatively, the a-bromo-y-alkyl tetronic acids are treated with dry hydrochloric acid in anhydrous ethanol to afford the corresponding u-chloro-y-alkyl tetronic acids by the procedure described by W. D. Kumlet, I. Am. Chem. Soc., 60, 857-859 (1938).

a-Hydroxy-y-alkyl tetronic acids are prepared by condensation of the sodio derivative of diethyl acetoxymalonate with an a-chloro hydrocarbon carboxylic acid chloride if [RZHC-Cl l in which R is methyl, ethyl, n-propyl, or isopropyl], subsequent ring closure with hydrolysis and decarboxylation using the method described by Ghose, J. Indian Chem. Soc., 23,311 (1946).

a-AlkOXy-y alkyl tetronic acids are prepared from the corresponding u-hydroxy-y-alkyl tetronic acids by refluxing the latter in a lower aliphatic alcohol such as methanol, ethanol, propanol, and the like, and in the presence of a strong acidic catalyst such as p-toluenesulfonic acid, for a period of 1 to 24 hours. In addition, the a-methoxy- 'y-alkyl tetronic acids can be prepared from the corresponding a-hydroxy-y-alkyl tetronic acids by methylation with diazomethane to afford a 2,3-dimethyl ether followed by hydrolysis with alkali, i.e. according to the method as described by Micheel and Schulte, Annalen, 519, (1935).

a-Alkoxycarbonyl-' -alkyl tetronic acids are prepared by condensing equal molar amounts of an a-chloro hydrocarbon carboxylic acyl chloride in which R is methyl, ethyl, n-propyl, or isopropyl], with ethyl alkoxymagnesiomalonate to afford an intermediary ethyl a-chloroacylmalonate and the latter intermediate is then cyclized at room temperature or by heating to afford the a-alkoxycarbonyl-y-alkyl tetronic acids, i.e. according to the method as described by L. J. Haynes, et al., J. Chem. Soc., 4661-4664 (1956).

a-Benzyl compounds of Formula II are prepared by treating a malonic acid ester 0 (t-butylO ("J-C Hi-t i-o E thyl) with a molar equivalent of sodium methoxide and benzyl bromide in benzene under refiux for about 18 hours and then treating the thus-obtained benzyl substituted ester with sodium methoxide and an acid chloride [ROCl in which R is methyl, ethyl, n-propyl, or isopropyl], in benzene at room temperature. The resulting oz-bCIlZYl-ozalkyl substituted ester is then refluxed in benzene in the presence of a small amount of p-toluenesulfonic acid to remove the t-butyl group followed by treatment with bromine in ether for about two hours at room temperature, removal of the ether solvent and refluxing of the residue in xylene for about 16-18 hours to afford a-benzyl-y-alkyl tetronic acid.

zx-Phenyl compounds of Formula II are prepared by treatment of phenylacetic acid ethyl ester with a molar equivalent of sodium hydride in benzene under reflux for about one hour followed by treatment with RCOCl, wherein R is methyl, ethyl, n-propyl, or isopropyl, in benzene at about room temperature for about 18 hours. The crude product is then treated with bromine as described above to afford a-phenyl-v-alkyl tetronic acid.

The following examples are provided to illustrate the present invention.

PREPARATION A To a solution of 1 g. of 'y-methyl tetronic acid in 10 ml. of anhydrou chloroform is added dropwise, a solution of 1 ml. of bromine and 10 ml. of anhydrous chloroform. The resulting mixture is allowed to stand at room temperature for a period of one-half hour, washed with 5% aqueous sodium bisulfite. The organic phase is dried and evaporated to dryness under reduced pressure to yield a residue of a-bromo-v-methyl tetronic acid which is recrystallized from ethyl acetate.

By repeating the above procedure with the exception of substituting tetronic acid for 'y-methyl tetronic acid, there is obtained u-bromo tetronic acid.

PREPARATION B To a solution of 1 g. of 'y-methyl tertonic acid in 10 ml. of anhydrous chloroform is added a solution of 1.05 molar equivalents of chlorine in 10 ml. of anhydrous chloroform. The resulting mixture is allowed to stand at room temperature for a period of one-half hour and then washed with 5% aqueous sodium bicarbonate. The organic phase is separated, dried and evaporated under reduced pressure to yield a residue of a-chloro-y-methyl tetronic acid which is recrystallized from ethyl acetate.

Similarly, using the above process the a-ChlOl'O tetronic acid can be prepared.

PREPARATION C To a solution of 19.8 g. of methyl cyanoacetate in 100 ml. of anhydrous benzene is added a freshly prepared solution of 4.6 g. of sodium in 50 ml. of methanol. After cooling the above mixture to C., there is then added dropwise 21.7 g. of propionyl chloride over a period of 30 minutes, and the resulting solution is held at 20 C. for 24 hours. The reaction mixture is then washed with Water, dried and evaporated under reduced pressure to afford a distillable oil containing methyl 2-cyano-3-oxo-valerate.

To a well-stirred solution of the above oil in 100 ml. of anhydrous ether is added dropwise 32 g. of bromine at such a rate that the solution continuously remains substantially clear. After the addition of the bromine, stirring is maintained for two hours. The resulting oil is then dissolved in 65 ml. of xylene, the ether solvent removed by distillation, and the resulting xylene mixture is refluxed for 17 hours. The xylene mixture is distilled in vacuo to a small volume which upon cooling deposits a precipitate of oc-CYflllO-y-HlthYl tetronic acid which is recrystallized from ethyl acetate.

By repeating the above procedure with the exception of substituting a molar amount of acetyl chloride for propionyl chloride, there is obtained a-cyano tetronic acid.

PREPARATION D To a solution of 35.6 g. of diethyl fluoromalonate in 100 ml. of anhydrous benzene is added a freshly prepared solution of 4.6 g. of sodium in 50 ml. of methanol. After cooling the above mixture to 0 C., there is then added dropwise 25.8 g. of chloroacetyl chloride over a period of one hour, and the resulting mixture is heated under reflux for one-half hour, cooled, washed with water, dried and evaporated under reduced pressure to afford a distillable oil containing diethyl zx-fluoro-a-chloroacetylmalonate.

To the latter oil is added 60 ml. of xylene, and the resulting mixture is held under reflux for a period of two hours. After cooling the reaction mixture, there is then added 120 ml. of petroleum ether to yield a-fluoro tetronic acid which is recrystallized from ethyl acetate.

By repeating the above procedure with the exception of substituting a molar amount of a-chloropropionyl chloride, there is obtained u-fluoro-v-methyl tetronic acid.

PREPARATION E To a refluxing solution of 5.7 g. of tetronic acid in 500 ml. of ethanol are added over a 30 minute period a solution of 80 g. of potassium hydroxide in 50 ml. of water and 25 ml. of dimethyl sulfate. Fifteen ml. and 5 ml. portions of the KOH solution and dimethyl sulfate, respectively, being added alternatively. The reaction mixture is then held at reflux for 45 minutes, cooled and then poured into ice water. Upon neutralization with hydrochloric acid, there is formed a precipitate of the O-methyl enol ether of tetronic acid.

A solution of 3.99 g. of the thus-obtained O-methyl enol ether of tetronic acid and 0.8 g. of benzoyl peroxide in 15 ml. of benzene is added over a period of one and onehalf hours, to a refluxing solution of g. of trichloromethane-sulfonyl chloride in ml. of benzene. The resulting reaction mixture is held at reflux for 15 hours. After removing the solvent by evaporation under reduced pressure, there is obtained a-trichloromethyl tetronic acid which is recrystallized from ethyl acetate:hexane.

By repeating the above procedure with the exception of substituting a molar amount of -methyl tetronic acid for tetronic acid, there is obtained oz-tI'iChlOIOmGthYl-ymethyl tetronic acid.

10 PREPARATION F To a refluxing solution of 5.7 g. of tetronic acid and 500 ml. of ethanol are added over a 30 minute period a solution of g. of potassium hydroxide in 50 ml. of water and 25 ml. of dimethyl sulfate. Fifteen ml. and 5 ml. portions of the KOH solution and dimethyl sulfate, respectively, being added alternatively.

The reaction mixture is then held at reflux for 45 minutes, cooled and then poured into ice water. Upon neutralization with hydrochloric acid there is formed a precipitate of the O-methyl enol ether of tetronic acid.

A mixture of 1 g. of O-methyl enol ether of tetronic acid and 112 g. of trifluoroiodomethane is irradiated with ultra-violet light from a high pressure mercury lamp at room temperature for hours in a sealed quartz tube. After removing the excess trifluoroiodomethane by evaporation under reduced pressure, there is obtained oc-tl'ifluoromethyl tetronic acid which is recrystallized from ethyl acetate:hexane.

By repeating the above procedure with the exception of substituting a molar amount of 'y-methyl tetronic acid for tetronic acid, there is obtained a.-trifluoromethyl-'ymethyl tetronic acid.

In the above outlined process for the preparation of the starting material, R is hydrogen, methyl, ethyl or isopropyl; R is hydrogen, hydroxy or esters, lower alkoxy, cyclopenyloxy, cyclohexyloxy, tetrahydropyran- 2-yloxy or tetrahydrofuran-2-yloxy; R is lower alkyl, hydrogen, hydroxy or esters, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2'-yloxy or tetrahydrofuran-2'-yloxy; and X is chloro or bromo.

To a freshly prepared solution of 4 g. of methylmagnesium bromide in 20 ml. of tetrahydrofuran is added a solution of 1 molar equivalent of benzaldehyde in 25 ml. of tetrahydrofuran and 15 ml. of ether. The resulting mixture is held at room temperature for 24 hours and then heated at reflux for two hours. The reaction mixture is cooled and then diluted with water. This mixture is acidified with HCl and stirred to decompose any excess Grignard reagent. The organic phase is separated and the aqueous layer extracted several times with ether. The combined ether extracts and organic phase is washed with water, dried and evaporated to furnish 2 phenyl- 2 hydroxyethane (3; R =R "=R =hydrogen). Two grams of 2-phenyl-2-hydroxyethane in 50 ml. of pyridine is added to a mixture of 1 g. of chromium trioxide in 10 ml. of pyridine. This mixture is allowed to stand at room temperature for 15 hours and is then diluted with ethyl acetate and filtered. The filtrate is washed with water, dried and evaporated to give methylphenyl ketone (4; R =R "=R "=hydrogen).

A freshly prepared solution of 3 g. of vinyl bromide in 3 ml. of tetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. of tetrahydrofuran to prepare a vinyl magnesium Grignard reagent. To this mixture is then added a solution of 1 g. of methylphenyl ketone in 25 ml. of tetrahydrofuran and 10 ml. of ether and the resulting mixture is held at room temperature for a period of 24 hours, then heated at reflux for one hour and then cooled. The reaction mixture is then poured into water, acidified with hydrochloric acid and stirred vigorously to decompose any excess Grignard reagent. The organic phase is then separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to yield 2 phenyl 2 hydroxybut-3-ene R =R =R "=hydrogen).

By repeating the process of this example using substituted benzaldehydes, e.g. 4 methoxybenzaldehyde, 4,6 dimethoxybenzaldehyde, 4 methoxy 6-methylbenzaldehyde, 6 methoxybenzaldehyde, 4,6 dihydroxybenzaldehyde and 6 methylbenzaldehyde in place of benzaldehyde, the corresponding substituted but-3-enc compounds are obtained, that is,

2- (4'-methoxyphenyl) -2-hydroxybut-3-ene,

2- (4',6'-dimethoxyphenyl) -2-hydroxybut-3-ene,

2- (4-methoxy-6'-methylphenyl -2-hydroxybut-3 -ene, 2- 6'-methoxyphenyl -2-hydroxybut-3 -ene,

2- 4',6'-dihydroxyphenyl )-2-hydroxy-but-3-ene and 2- 6'-methylphenyl) -2-hydroxybut-3-ene, respectively.

By repeating the above procedure using ethylmagnesium bromide, n-propylmagnesium bromide and isobutylmagnesium bromide in place of methylmagnesium bromide, there is obtained the corresponding compounds of Formula 5 above where R is methyl, ethyl and i-propyl, respectively.

EXAMPLE 2 A mixture of 11.8 g. of thiourea and 100 ml. of acetic acid is warmed on a steam bath until th'e mixture becomes homogeneous. The solution is then cooled to room temperature and to it is then added 1 molar equivalent of 2-phenyl-2-hydroxybut-3-ene. The resulting mixture is agitated until the mixture again becomes homogeneous. The acetic acid is then removed by heating (SO-60 C.) under reduced pressure. The residue is poured with stirring into 70 ml. of ether. The resulting precipitate is collected and dried to yield 3-phenylbut-2- enyl isothiouronium acetate (I; R =R =R =hydrogen).

By repeating the above process using other compounds of Formula 5 prepared by the procedure of Example 1 as the starting material, for example,

2- 4'-methoxyphenyl) -2-hydroxy-but-3-ene,

3- (4 '-methoxyphenyl )-3-hydroxypent- 4-ene,

4 4',6'-dimethoxyphenyl) -4-hydroxy-2-methylhex-S-ene, 4- (4'-methoxyphenyl -4-hydroxy-2-methylhex-5 -ene, 4-phenyl-4-hydroxy-2-methylhex-S-ene,

4-(4',6'- dimethoxyphenyl -4'hydroxy-2-methylhex-S-ene, 3- (4',6'-dimethoxyphenyl) -3 -hydroxypent-4ene, and

4- (4-methoxy-6'-methylphenyl) -4-hydroxyhex-5-ene,

the corresponding isothiouronium acetates are obtained.

EXAMPLE 3 (A) To a freshly prepared solution of 4 g. of n-propylmagnesium bromide in 30 ml. of tetrahydrofuran is added a solution of 1 molar equivalent of 4-methoxybenzaldehyde in 25 ml. of tetrahydrofuran and 15 ml. of ether. The resulting mixture is held at room temperature for 24 hours and then heated at reflux for two hours. The reaction mixture is cooled, diluted with water and acidified with hydrochloric acid and stirred to decompose any excess Grignard reagent. The organic phase is washed with water, dried and evaporated to furnish 4-(4'-methoxyphenyl) 4 hydroxybutane (3; R =ethyl, R "=OCH R '=hydrogen). Two grams of 4-(4'-methoxyphenyl)-4-hydroxybutane in 50 ml. of pyridine is added to a mixture of 1 g. of chromium trioxide in 10 ml. of pyridine. This mixture is allowed to stand at room temperature for about hours and is then diluted with ethyl acetate and filtered. The filtrate is washed with water, dried and evaporated to give n-propyl 4-methoxyphenyl ketone (4; R =ethyl, R OCH R =hydrogen). This compound is subjected to the procedure of 12 Example 7 to afford n-propyl 4-hydroxyphenyl ketone (4; R =ethyl, -R "=OH, R hydrogen).

By repeating the above procedure using 4,6-dimethoxybenzaldehyde and 4-methoxy--methylbenzaldehyde as the starting material in place of 4-methoxybenzaldehyde, there is obtained n-propyl 4,6-dihydroxyphenyl ketone (4; R =ethyl, R "=R =hydroxy) and n-propyl 4-hydroxy-6-methylphenyl ketone (4; R =ethyl, R -=hydroxy, R =CH respectively.

(B) A mixture of 1 g. of n-propyl 4-hydroxyphenyl ketone, 3 ml. of pyridine and -1.5 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield n-propyl 4-acetoxyphenyl ketone which can be further purified by recrystallization.

By using other carboxylic anhydrides in place of acetic anhydride, for example, propionic anhydride, n-butyric anhydride, n-caproic anhydride, trimethylacetic anhydride, and the like, the corresponding ester is obtained.

By repeating the above procedure using n-propyl 4,6- dihydroxyphenyl ketone and n-propyl 4-hydroxy-6-methylphenyl ketone as the starting material, there is obtained n-propyl 4,6-diacetoxyphenyl ketone and n-propyl 4- acetoxy-6-methylphenyl ketone.

(C) A freshly prepared solution of 3 g. of vinyl bromide in 3 ml. of tetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. of tetrahydrofuran to prepare a vinyl magnesium Grignard reagent. To this mixture is then added a solution of 1 g. of n-propyl 4-acetoxyphenyl ketone in 25 ml. of tetrahydrofuran and 10 ml. of ether. The resulting mixture is held at room temperature for a period of 24 hours, then heated at reflux for one hour and then cooled. The reaction mixture is then poured into water, acidified With hydrochloric acid and stirred to decompose any excess Grignard reagent. The organic phase is then separated and the aqueous layer is extracted several times with ether. The combined ether phases are washed with water to neutrality, dried over sodium sulfate and evaporated to yield 4-(4-acetoxyphenyl)-4-hydroxyhex-5-ene (5; R =ethyl, R "=acetoxy, R =hydrogen).

By repeating the above procedure using n-propyl 4,6- diacetoxyphenyl ketone and 4-acetoxy-6-methylphenyl ketone as the starting material, there is obtained 4-(4,6'- diacetoxyphenyl)-4-hydroxyhex-5-ene and 4-(4'-acetoxy- 6'-methylphenyl)-4-hydroxyhex-5-ene, respectively.

EXAMPLE 4 A solution of one chemical equivalent of n-propyl 4- hydroxyphenyl ketone in 25 ml. of benzene is heated to reflux and about 2 ml. removed by distillation to eliminate moisture. The mixture is cooled to room temperature and two chemical equivalents of sodium hydride are added, followed by dropwise addition of two chemical equivalents of cyclopentyl bromide in 10 ml. of benzene over a period of 20 minutes. The mixture is allowed to reflux for 20 hours after which time the precipitate of sodium bromide is removed by filtration and the organic phase dried and evaporated to yield n-propyl 4-cyclopentyloxyphenyl ketone (4; R =ethyl, R "=cyclopentyloxy, R =hydrogen).

'By repeating the above procedure using an equivalent amount of cyclohexyl bromide in place of cyclopentyl bromide, there is obtained n-propyl 4-cyclohexylphenyl ketone.

Similarly, using the other hydroxy compounds of Example 3(A) in the above procedure, there is obtained npropyl 4,6-dicyclopentyloxyphenyl ketone and n-propyl 4-cyclopentyloxy-o-phenyl ketone, respectively.

'By subjecting the above cyclopentyl and cyclohexyl ethers to the procedure of Example 3(C), there is obtained 4 (4-cyclopentyloxyphenyl)-4-hydroxyhex-S-ene, 4- (4-cyclohexyloxyphenyl -4-hydroxyhex-5-ene, 4- (4',6- dicyclopentyloxyphenyl)-4-hydroxyhex-5-ene, 4-(4,6-di- 13 cyclohexyloxyphenyl) 4 hydroxyhex-S-ene, 4(4'-cyclopentyloxy-6-methylphenyl) 4 hydroxyhex-S-ene and 4- (4' cyclohexyloxy- '-methylphenyl) 4 hydroxyhex-S- ene, respectively.

EXAMPLE 1.5 ml. of dihydropyran is added to a solution of 1 g. of n-propyl 4-hydroxyphenyl ketone in ml. of henzene. About 1 ml. is removed by distillation to eliminate moisture and 0.3 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina to yield n-propyl 4-(tetrahydropyran-2'-yloxy)- phenyl ketone (4; R =ethyl, R "=tetrahydropyran-2'- yloxy, R "=hydrogen).

A freshly prepared solution of 3 g. of vinyl bromide in 3 ml. of tetrahydrofuran is added to 0.5 g. of magnesium in 5 ml. of tetrahydrofuran to prepare a vinyl magnesium Grignard reagent. To this mixture is then added a solution of 1 g. of n-propyl 4-(tetrahydropyran-2'-yloxy)- phenyl ketone in 25 ml. of tetrahydrofuran and 10 ml. of ether and the resulting mixture is held at room temperature for a period of 24 hours, then heated a reflux for one hour and then cooled. The reaction mixture is then poured into water and hydrochloric acid is added to decompose any excess Grignard reagent. The organic phase is then separated and the aqueous layer is extracted several times with ether. The combined ether phases are washed with water to neutrality, dried over sodium sulfate and evaporated to yield 4-[4'-(tetrahydropyran-2"-yloxy)- phenyl]-4-hydroxyhex-5-ene (5; R =ethyl, R "=tetrahydropyran-2-yloxy, R =hydrogen) By using dihydrofuran in the above procedure in place of dihydropyran, the corresponding tetrahydrofuran-2'-yl ether is obtained. By use of this procedure the other hydroxy compounds of Formula 4 can be converted into the tetrahydropyranyl and tetrahydrofuranyl ethers.

EXAMPLE 6 The procedure of Example 2 is repeated using 4-(4'- acetoxyphenyl) 4'hydroxyhex-5-ene, 4-(4',6-diacetoxyphenyl)-4-hydroxyhex-5-ene and 4-(4'-acetoxy-6-methylphenyl)-4-hydroxyhex-5-ene as the starting material and there is obtained 3-(4'-acetoxyphenyl)-hex-2-enyl isothiouronium acetate, 3-(4',6'-diacetoxyphenyl)-hex-2-enyl isothiouronium acetate and 3-(4-acetoxy-6'-methylpheny1)-hex-2-enyl isothiouronium acetate, respectively.

EXAMPLE 7 A mixture of 5 g. of n-propyl 4-methoxyphenyl ketone, 10 g. of 48% aqueous hydrobromic acid and ml. of glacial acetic acid is refluxed for two hours. The mixture is cooled, neutralized by the addition of dilute aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride extracts are combined, washed with water, dried and evaporated to give n-propyl 4-hydroxyphenyl ketone.

EXAMPLE 8 To a solution of 12.5 g. of 3-phenylbut-2-enyl isothiouronium acetate in a mixture of 80 ml. of ethanol and 100 ml. of water, there is added a solution of 1 molar equivalent of 'y-methyl tetronic acid in 20 ml. of ethanol. Immediately, the reaction mixture is diluted by adding an additional 80 ml. of water, stirred and allowed to stand at room temperature for a period of 24 hours. The reaction mixture is then heated at about 60 C. for 10 hours and then cooled to 5 C. for two hours, and the thusformed precipitate collected by filtration to yield 11-(3- phenylbut-Z-enyl)-'y-dimethyl tetronic acid (IH; R =CH R '=R =R =R =hydrogen).

14 EXAMPLE 9 To a solution of 12.5 g. of 3-(4'-methoxyphenyl)-5- methylhex-Z-enyl isothiouronium acetate in a mixture of ml. of ethanol and ml. of water, there is added a solution of 1 molar equivalent of 'y-methyl tetronic acid in 20 ml. of ethanol. Immediately, the reaction mixture is diluted with 80 ml. of water and then stirred and allowed to stand at room temperature for 24 hours. The reaction mixture is then cooled to 5 C. for two hours and he thus-formed precipitate collected by filtration to yield a [3 (4'-methoxyphenyl)-5-methylhex-2-enyl]-'y-methyl tetronic acid (HI; R =CH R =isopropyl, R =OCH R =R =hydrogen).

CHsO

By use of the process of this example other isothiouronium acetates, eg

3-- (4',6-dimethoxyphenyl) -hex-2-enyl isohtiouronium acetate,

3-(4'-methoxy-6'-methylphenyl)-hex-2-enyl isothiouronium acetate,

3-(4,6-dimethoxyphenyl)-5-methylhex-2-enyl isothiouronium acetate,

3- 4'-methoxy-6'-methylphenyl) -5-methylhex-2-enyl isothiouronium acetate or 3-(4',6'-dimethoxyphenyl) -pent-2-enyl) isothiouronium acetate,

prepared according to the procedure of Example 2, the corresponding products are obtained, that is tat-[3-(4',6'-dimethoxyphenyl)-hex-2-enyl]-'y-methyl tetronic acid,

oc-[3-(4'-methoxy-6'-methylphenyl)-hex-2-enyl]-'y-methyl tetronic acid,

a-[3-(4,6'-dimethoxyphenyl)-5-methylhex-2-enyl]- -methyl tetronic acid,

a-[3-(4'-methoxy-6'-methylpheny1)-5-methylhex-2-enyl]- 'y-methyl tetronic acid and a-[3-(4',6'-dimethoxyphenyl)-pent-2-enyl]-'y-methyl tetronic acid, respectively.

I CH3 EXAMPLE 11 To a solution of l g. of a-[3-(4',6'-dimethoxyphenyl)- but-Z-enyH-y-methyl tetronic acid in 20 m1. is added 1 ml. of 15% HCl (by weight). The resulting mixture is stirred and allowed to stand at room temperature for 17 hours. The reaction mixture is extracted several times with ether. The ether extracts are combined, washed well with water,

dried and evaporated to give -(4',6'-dimethoxyphenyl)- 3 methyl 6,7,8,9 tetrahydro-isobenzofuran-l-one (IV;

The procedure of Example 8 is repeated using oc-fiUOIO- 'y-methyl tetronic acid, a-chloro tetronic acid, u-hydroxy tetronic acid, a-trifluoromethyl tetronic acid and a-benzyl- 'y-methyl tetronic acid in place of 'y-methyl tetronic acid and there is obtained a-(3-phenylbut-2-eny1)-a'-fluoro-' -methyl tetronic acid, a-(3-phenylbut-2-enyl)-u'-chloro tetronic acid, a-(3-phenylbut-2-enyl)-a'-hydroxy tetronic acid, a-(3-phenylbut-2-enyl)-u-trifiuoromethyl tetronic acid and 25 a-(3-phenylbut-2-enyl)-a'-benzyl-'y-methyl tetronic acid which are subjected to the procedure of Example 10 to afford the corresponding enol lactones, that is,

S-phenyl-3-methyl-8-fluoro-6,7,'8,9-tetrahydroisobenzofuran-l-one,

5-phenyl-8-chloro-6,7,8,9-tetrahydro-isobenzofuranl-one,

5-pheny1-8-hydroxy-6,7,8,9-tetrahydro-isobenzofuranl-one,

5-phenyl-8-trifluoromethyl-6,7,8,9-tetrahydroisobenzofuran-l-one and S-phenyl-3-methyl-8-benzyl-6,7,8,9-tetrahydro-isobenzofuran-l-one, respectively.

EXAMPLE 13 By repeating the procedure of Example 9 using ozfluoro-y-methyl tetronic acid, u-trichloromethyl-v-methyl tetronic acid, a-methoxy-y-methyl tetronic acid, a-cyano tetronic acid and a-phenyl-v-methyl tetronic acid in place of 7-methyl tetronic acid, there is obtained 45 respectively, which are subjected to the procedure of Example 11 to afford the corresponding enol lactones, that is,

5- (4'-methoxyphenyl) -3-methyl-8-fluoro-6-8-7-9-tetrahydro-isobenzofuran-l-one,

5 (4methoxyphenyl 3-methyl-8-trichloromethyl-6,7,8,9-

tetrahydro-isobenzofuranl-one,

5-(4'-methoxyphenyl)-3-methyl-8-methoxy-6,7,8,9-

tetrahydro-isobenzofuranl-one,

5 (4'-methoxyphenyl '8-cyano-6,7,8,9-tetrahydro-isobenzofuranl-one, and

5- (4-methoxyphenyl) -3-methyl-8-phenyl-6,7,8,9-tetrahydro-isobenzofuran-l-one, respectively.

In a similar manner, the other isothiouronium acetates herein, see Example 9 for example, can be converted into the corresponding substituted tetronic acids and enol lactones.

16 EXAMPLE 14 To a solution of 15 g. of a-[3-(4'-methoxyphenyl)-5- methylhex-Z-enyl]w-methyl tetronic acid in 200 ml. of water-dioxane (1:1), under nitrogen, there is added 200 mg. of sodium hydroxide followed by a solution of 4 g. of sodium methoxide dissolved in 16 ml. of methanol. Then 12 ml. of 40% aqueous formaldehyde is added to this solution and the mixture stirred for 12 hours. After cooling, the reaction mixture is then extracted with methylene chloride (2X 10 ml.). The organic phase is dried and evaporated to dryness to yield u-[3-(4'-methoxyphenyl) 5 methylhex 2 enyl]-u'-hydroxymethyl-'ymethyl tetronic acid which is subjected to the procedure of Example 11 to afiord 5-(4-methoxyphenyl)-4-isopropyl-8-hydroxymethyl-3-methyl 6,7,8,9 tetrahydroisobenzofuran-l-one.

By repeating the above procedure using other compounds of Formula III in which R is hydrogen as the starting materials, the corresponding u'-hydroxymethyl derivatives and 8-hydroxymethyl derivatives, respectively, are obtained. For example,

a-(3-phenylbut-2-enyl) t-methyl tetronic acid,

a- [3- (4',6'-dimethoxyphenyl) -but-2-enyl] -'y-methyl tetronic acid,

a- 3- (4',6-dimethoxyphenyl) -hex-2-enyl] -'y-methyl tetronic acid,

a-[3-(4'-methoxy-6'-methylphenyl)-hex-2-enyl]-' methyl tetronic acid, and

a- [3-(4',6'-dimethoxyphenyl)-pent-2-enyl]-7-methy1 tetronic acid are converted using the above procedure into, firstly,

a-(3-phenylbut-2-enyl)-a'-hydroxymethyl-'y-methyl tetronic acid,

a-[3-(4',6'-dimethoxyphenyl)-but-2-enyl]-a'-hydroxymethyl-'y-methyl tetronic acid,

a- 3 (4',6'-dimethoxyphenyl) -hex-2-enyl] -u'-hydroxymethyl-'y-methyl tetronic acid,

a- 3- (4'-meth0xy-6-methylphenyl -hex-2-enyl] -11- hydroxymethyly-methyl tetronic acid, and

u- [3- (4, '-dimethoxyphenyl -pent-2-enyl] -a'-hydroxymethyl-'y-methyl tetronic acid,

respectively and secondly, the corresponding enol lactones, i.e.

5-phenyl-3-methyl-8-hydroxymethyl-6,7,8,9=tetrahydroisobenzofuran-l-one,

5-(4', -dimethoxyphenyl)-3-methyl-8-hydroxymethyl- 6,7,8,9 tetrahydro-isobenzofuran-l-one,

5-(4,6'-dimethoxyphenyl)-3-methyl-8-hydroxymethy1- 4-ethyl-6,7,8,Q-tetrahydro-isobenzofuran-l-one,

5- 4'-methoxy-6'-methylphenyl -3 -methyl-8-hydroxymethyl-4ethyl-6,7,8,9-tetrahydro-isobenzofuran-l-one, and

5-(4',6-dimethoxyphenyl-3,4-dimethy1-8-hydroxymethyl- 6,7,8,9-tetrahydro-isobenzofuran-l-one, respectively.

EXAMPLE 15 To a solution of 1 g. of a-[3-(4'-methoxyphenyl)-5- methylhex-2-enyl]-a'-hydroxymethyl 'y methyl tetronic acid in 30 ml. of anhydrous methylene chloride, is added 1 g. of N-(2-chloro-1,1,2-trifluoroethyl) diethylamine, and the resulting reaction mixture is held at reflux for a period of five hours. After cooling, the reaction mixture is poured into Water and extracted with several portions of ether. The organic phase is separated, dried and evaporated to dryness to yield a-[3-(4'-methoxyphenyl)-5- methylhex-Z-enyl]-a'-fluoromethyl-,'-methyl tetronic acid.

By repeating the above procedure using the other bydroxymethyl substituted compounds of Example 14, there are obtained the corresponding fluoromethyl compounds.

EXAMPLE 16 To a solution of 1 g. of u-[3-(4'-methoxyphenyl)-S- methylhex-Z-enyl]-a'-hydroxymethyl tetronic acid in 50 17 ml. of anhydrous ether, previously cooled to C., is added 1.5 ml. of thionyl chloride. The reaction mixture is held at 0 C. for 15 minutes, warmed to room temperature and washed with an aqueous solution of sodium bicarbonate. The organic phase is separated, dried and evaporated to dryness to yield a-[3-(4-methoxyphenyl)- methylhex-2-enyl] -a-chloromethyl-'y-methyl tetronic acid. By repeating the above procedure using the other hydroxymethyl substituted compounds of Example 14 as the starting material, the corresponding chloromethyl substituted compounds are obtained.

EXAMPLE 17 A mixture of 0.5 g. of -phenyl-3-methyl-8-hydroxymethyl-6,7,8,9-tetrahydro-isobenzofuran-l-one in 60 ml. of ethanol and 20 ml. of 1 N aqueous sodium hydroxide solution is allowed to stand at room temperature for two hours. This reaction mixture is then acidified by the addition of 0.1 N aqueous hydrochloric acid. The resulting acidic mixture is then extracted several times with ether. The ether extracts are combined, dried and evaporated under reduced pressure to give cis 5-phenyl-35-methyl-3ghydroxy 8 hydroxymethyl 3,9,6,7,8,9 hexahydro-isobenzofuran-l-one represented as follows.

0H 11 (3H2 CH2 I? ..-COOH 3 0 W ..c I

H H on EXAMPLE 18 To a substantially anhydrous solution of 1 g. of 5-(4- methoxyphenyl) 4 isopropyl 8 hydroxymethyl 3- methyl 6,7,8,9 tetrahydro isobenzofuran-l-one and 1.85 g. of N,N'-dicyclohexylcarbodiimide in 15 ml. of dimethyl sulfoxide there is added 0.15 g. of anhydrous orthophosphoric acid. The resulting reaction mixture is held at room temperature for two hours, then 0.62 g. of N,N'-dicyclohexylcarbodiimide is added. The reaction mixture is then allowed to stand for an additional hour. After removing the solvent by evaporation under reduced pressure, there is obtained 5 (4-methoxypheny1)-4-isopropyl-8- formyl-3methyl-6,7,8,9-tetrahydro-isobenzofuran-l-one.

By repeating the above procedure using the other hydroxymethyl substituted compounds of Example 14 as the starting material, there are obtained the corresponding formyl substituted compounds.

As an alternative to the foregoing procedure, the hydroxymethyl group can be converted into formyl using chromic oxide in pyridine.

EXAMPLE 19 A solution of 0.66 g. of 5-(4'-methoxyphenyl)-4-isopropyl-8-formyl-3-rnethyl 6,7,8,9 tetrahydro-isobenzofuran-l-one in 25 ml. of dioxane in a stainless steel shaker tube is treated at 70" C. with two molar equivalents of sulfur tetrafiuoride. The shaker tube is sealed, allowed to warm to room temperature and then held at room temperature for a period of 20 hours. The shaker tube is then cooled and the contents of the tube poured carefully into ice water and treated with an excess of sodium bicarbonate. The aqueous phase is extracted with several portions of methylene chloride. The organic phase is separated, dried and evaporated to dryness under reduced pressure to yield 5-(4'-methoxyphenyl)-4-isopropyl-8-difluoromethyl-3-methyl-6,7,8,9 tetrahydro-isobenzofuranl-one.

In a similar manner, by repeating the above procedure using other formyl compounds of Example 18 as the starting material, the corresponding difiuoromethyl compounds are obtained.

18 EXAMPLE 20 A mixture of 2 g. of 5-(4'-methoxyphenyl)-4-isopropyl- 8-formyl-3-methyl-6,7,8,9 tetrahydro isobenzofuran-lone and 3 g. of phosphorus pentachloride, ml. of carbon tetrachloride is held at reflux for a period of two hours. The reaction mixture is cooled, washed with several portions of 5% aqueous sodium bicarbonate solution, and then with several portions of water. The organic phase is separated, dried and evaporated to dryness under reduced pressure to yield 5-(4-methoxyphenyl)-4-isopropyl-8-dichloromethyl-3-methyl-6,7,8,9 tetrahydro-isobenzofuran-l-one.

By subjecting the other formyl compounds of Example 18 to the above process, the corresponding dichloromethyl compounds are obtained.

EXAMPLE 21 A mixture of 307 mg. of cris 5-phenyl-3-methyl-3- hydroxy-8-hydroxymethyl 3,9,6,7,8,9 hexahydro isobenzofuran-l-one, 1 ml. of methyl iodide and 7 ml. of dimethylacetamide is stirred in the dark for five hours. Then, excess methyl iodide is removed by evaporation under reduced pressure. The reaction mixture is then poured into water and the mixture extracted several times with ether. The ether extracts are combined, washed with water and then dilute aqueous sodium thiosulfate solution, dried and evaporated to furnish the methyl ester of cis 4-phenyl 1 hydroxymethyl-2-acetylcyclohex-3-enecarboxylic acid which can be crystallized from benzene: hexane (VI'; R =hydroxymethyl, R '=CH Similarly, by repeating the above procedure using other lower alkyl iodides or bromides, e.g. ethyl iodide and the like, in place of methyl iodide, the corresponding lower alkyl esters are obtained.

EXAMPLE 22 A mixture of 1 g. of the methyl ester of cis 4-phenyll-hydroxymethyl-2-acetylcyclohex-3-enecarboxylic acid, 4 ml. of pyridine and 4 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield the methyl ester of cis 4-phenyl-l-acetyloxymethyl- 2-acetylcyclohex-3-enecarboxylic acid.

Similarly, by using an equivalent amount of other lower carboxylic anhydrides in place of acetic anhydride, for

example, propionic anhydride, n-butyric anhydride, n-caproic anhydride, trimethylacetic anhydride, and the like, the corresponding ester is obtained.

EXAMPLE 23 Into the cathode compartment of a divided electrolysis cell provided with a cellulose dialysis membrane, lead electrodes (each electrode measuring 2 cm. x 5 cm. x 1.6 mm.) and a stirrer, there is added 20 mg. of the methyl ester of cis 4-phenyl-l-acetyloxymethyl-2-acetylcyclohex- 3-enecarboxylic acid and a mixture of 15 ml. of dioxane and 15 ml. of 10% aqueous sulfuric acid (by weight). An additional amount of a mixture of 15 ml. of dioxane and 15 ml. of 10% aqueous sulfuric acid is added to the cell. A current density of 0.02 amps/em. is applied for a period of five hours. The reaction mixture is then removed from the cell and concentrated under reduced pressure to a small volume which is then extracted several times with ether. The ether extracts are combined, washed with water and a 5% aqueous sodium bicarbonate solution, dried and evaporated to dryness to furnish the methyl ester of cis 4-phenyl-1-acetyloxymethyl-Z-ethylcyclohexl3-enecarboxylic acid.

By repeating the process of this example using the cis lactol of Example 17 and the cis keto ester of Example 21 as the starting material, there is obtained cis 4-phenyl- 1-hydroxymethyl-2-ethylcyclohex 3 enecarboxylic acid and the methyl ester of cis 4-pheny1-l-hydroxymethyl-Z- ethylcyclohex-3-enecarboxylic acid, respectively.

EXAMPLE 24 A solution of 1 g. of cis 4-phenyl-l-hydroxymethyl-Z- ethylcyclohex-3 -enecarboxylic acid in dry benzene is chilled in an ice-bath and then saturated with dry hydrogen chloride. This reaction mixture is allowed to stand at room temperature for four hours. The solvent is removed by evaporation to yield cis 4-phenyl-l-hydroxymethyl-Z-ethylcyclohex-4-enecarboxylic acid.

EXAMPLE 25 A suspension of 0.3 g. of palladium-on-carbon catalyst in 50 ml. of methanol is hydrogenated for 30 minutes. A solution of 2 g. of cis 4-phenyl-1-hydroxymethyl- 2-ethylcyclohex-3-enecarboxy1ic acid in 150 ml. of methanol is added and hydrogenated with agitation until the uptake of hydrogen ceases. The catalyst is removed by filtration and the filtrate evaporated to yield cis 4-phenyl- 1 hydroxymethyl 2 ethylcyclohexanecarboxylic acid (VIII; R =hydroxymethyl, R =CH R =R =R =hydrogen).

EXAMPLE 26 A mixture of 670 mg. of 5-(4,6-dimethoxyphenyl)-3- methyl-S-hydroxymethyl 6,7,8,9 tetrahydro isobenzofuran-l-one in 70 ml. of dioxane and 45 ml. of 0.1 N aqueous sodium hydroxide is allowed to stand at 20 C. for 36 hours. The solvents are then removed by evaporation under reduced pressure. The resulting residue is diluted with water and acidified by adding dilute hydrochloric acid. This aqueous mixture is extracted several times with ether. The ether extracts are combined and then evaporated to dryness to yield a mixture of trans 4- (4',6'-dimethoxyphenyl) 1 hydrOXymethyI-Z-acetylcyclohex-3-enecarboxylic acid and cis 5-(4',6-dimethoxyphenyl)-3g-methyl-3g-hydroxy-S-hydroxymethyl 3,9,6,7,- 8,9-hexahydro-isobenzofuran-l-one which is separated by fractional crystallization using benzenezhexane to give trans 4-(4',6'-dimethoxyphenyl) 1 hydroxymethyl-2- acetylcyclohex-B-enecarboxylic acid.

By subjecting the above prepared trans keto acid to the reduction process of Example 23, there is obtained trans 4-(4',6' dimethoxyphenyl) 1 hydroxymethyl-Z- ethylcyclohex-3-enecarboxylic acid.

EXAMPLE 27 A mixture of 1 g. of 5-phenyl-3-methyl-8-hydroxymethyl-6,7,8,9-tetrahydro-isobenzofuran-l-one, 0.4 g. of potassium carbonate and 100 ml. of aqueous ethanol (1:1) is refluxed for four hours. The mixture is then cooled to room temperature, concentrated to dryness under vacuum and the residue chromatographed on silica gel to yield the potassium salt of trans 4-phenyl-l-hydroxyrnethyl-2-acetylcyclohex-3-enecarboxylic acid which is subjected to the process of Example 21 to aiford the methyl ester. By use of the process of Example 23, the thus-obtained methyl ester is converted into the methyl ester of trans 4-phenyll-hydroxymethyl 2 ethylcyclohex-3-enecarboxylic acid which can be converted into the methyl ester of the corresponding cyclohex-4-enecarboxylic acid and cyclohexanecarboxylic acid using the procedures of Examples 24 and 25, respectively.

EXAMPLE 28 A mixture of 300 mg. of the methyl ester of cis 4-phenyll-hydroxymethyl 2 ethylcyclohex 3 enecarboxylic acid, 3.1 g. of potassium hydroxide, 7 ml. of ethanol and 7 ml. of water in a sealed tube is heated at about 180 C. for about 45 minutes. The reaction mixture is allowed to cool and is then poured into water. The resulting mixture is then acidified by the addition of dilute aqueous hydrochloric acid and extracted several times with ethyl acetate. The ethyl acetate extracts are combined, dried and evaporated to give cis 4-phenyl-l-hydroxymethyl-Z- ethylcyclohex-3-enecarboxylic acid.

By use of the process of this example, other methyl esters of this invention can be converted into the free acid.

EXAMPLE 29 A solution of 1 g. of cis 4-(4',6'-dimethoxyphenyl)-1- hydroxymethyl-2-ethylcyclohex 3 enecarboxylic acid in 20 ml. of CCL, is mixed with 2 g. of triphenylphosphine. The reaction mixture is held at 25 C. for 12 hours. The mixture is then poured into ice water, filtered and the filtrate extracted with ether. The ether extracts are dried and evaporated to yield cis 4-(4',6'-dimethoxyphenyl)-1- hydroxymethyl-2-ethylcyclohex-3-enecarboxylic acid chloride.

EXAMPLE 30 A solution of 1 g. of cis 4-(4',6'-dimethoxyphenyl)-1- hydroxymethyl-Z-ethylcyclohex 3 enecarboxylic acid in 30 ml. of anhydrous methylene chloride is mixed with 1 g. of N (Z-chloro-1,1,2-trifluoroethyl)diethylamine. The reaction mixture is heated at reflux for five hours. The mixture is then poured into ice water, filtered and extracted with ether. The ether extracts are combined, dried and evaporated to yield cis 4-(4',6'-dimethoxyphenyl)-1- hydroxymethyl 2 ethylcyclohex 3 enecarboxylic acid fluoride.

EXAMPLE 31 A mixture of 1 g. of the methyl ester of cis 4-phenyll-acetyloxymethyl-2-ethylcyclohex 3 enecarboxylic acid in 20 ml. of anhydrous tetrahydrofuran is cooled to C. in a Dry Ice-acetone bath and treated with a previously cooled solution of 0.6 g. of lithium aluminum hydride in 20 ml. of anhydrous tetrahydrofuran. The reaction mixture is then allowed to warm to room temperature and is then heated at reflux for 15 minutes. The reaction mixture is then cooled and poured into ice water and extracted several times with ethyl acetate. The ethyl acetate extracts are combined, washed with water to neutrality, dried and evaporated to dryness to yield cis 4-phenyl-l-acetyloxymethyl-l-hydroxymethyl 2 ethylcyclohex-3-ene which may be further purified through recrystallization from acetonezhexane.

EXAMPLE 32 To a solution of 1 g. of cis 4-phenyl-l-acetyloxymethyl- 1-hydroxymethyl-2-ethylcyclohex-S-ene in 25 ml. of pyridine, previously cooled to 0 C., there is added dropwise a cooled solution (0 C.) of 1 g. of chromic trioxide in 25 ml. of pyridine. The resulting reaction mixture is held at 0 C. for a period of 24 hours, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate is washed with water, dried and evaporated to yield cis 4phenyl-l-acetyloxymethyl-l-formyl 2 ethylcyclohex- 3-ene which can be recrystallized from acetone:hexane.

EXAMPLE 33 A solution of 1 g. of cis 4-(4',6'-dimethoxyphenyl)-1- hydroxymethyl 2-ethylcyclohex-3-enecarboxylic acid, 2 ml. of thionyl chloride in 20 ml. of benzene is held at reflux for a period of two hours. The reaction mixture is cooled and evaporated. The residue is dissolved in anhydrous dioxane and the solution saturated with a stream of anhydrous ammonia. Water is then added after 24 hours and the product isolated by filtration to afford cis 4-(4,6'- dimethoxyphenyl) l hydroxymethyl 2 ethylcyclohex-3-enecarboxylic acid amide.

'EXAMPLE 34 A mixture of 5 g. of cis 4-(4'-methoxyphenyl)-l-hydroxymethyl 2 methyl 3 ethylcyclohex 4 enecarboxylic acid, 15 g. of 48% aqueous hydrobromic acid and 30 ml. of glacial acetic acid is refluxed for two hours. The mixture is cooled, neutralized by the addition of dilute aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride extracts are combined,

21 washed with water, dried and evaporated to give cis 4- (4' hydroxyphenyl) 1 hydroxymethyl 2 methyl-3- ethylcyclohex-4-enecarboxylic acid.

EXAMPLE 35 A mixture of 5 g. of oz-[3-(4','6'-dimethoxyphenyl)- hex 2 enyl] oz hydroxymethyl-y-methyl tetronic acid in 140 ml. of 98% formic acid is held at room temperature for three hours and then poured onto an excess of ice. After filtration and washing with water, there is obtained 5 (4',6 dimethoxyphenyl) 4 ethyl-3-methyl- 8 hydroxymethyl 6,7,8,9 tetrahydro-isobenzofuranl-one.

By repeating the process of this example with the exception of using an equivalent amount of other compounds of Formula III as the starting material, the corresponding enol lactones of Formula IV are obtained.

EXAMPLE 36 By repeating the procedure of Example 17 using 5-phenyl-3 -methyl-8-fiuoro-6,7,8,9 tetrahydro-isobenzofuran-1-one,

5-phenyl-8-chloro-6,7,8,9-tetrahydro-isobenzofuran-1- one,

S-phenyl- 8-hydroxy-6,7,8,9-tetrahydro-isobenzofuranl-one,

5 phenyl 8 trifluoromethyl 6,7,8,9 tetrahydro-isobenzofuran-l-one,

5-pheny1-3-methyl-8-benzyl-6,7,8,9 tetrahydro-isobenzofuran-l-one,

5- (4'-methoxyphenyl)-3-methy1-8-fluoro-6,7,8,9-tetrahydro-isobenzofuran-l-one,

5-(4'-methoxyphenyl)-3-rnethyl-8-trichloromethyl-6,7,8,9-

tetrahydro-isobenzofuran-l-one,

5-(4'-methoxyph'enyl)-3-methyl-8-methoxy'6,7,8,9-tetrahydro-isobenzofuran-l-one,

5- 4-methoxyphenyl -8-cyano-6,7,8,9-tetrahydroisobenzofuran-l-one, and

5-(4'-methoxyphenyl)-3-n1ethyl-8-phenyl-6,7,8,9-tetrahydro-isobenzofuran-l-one as the enol lactone starting material, there are obtained the corresponding cis lactols, that is,

cis 5-phenyl-3g-methyl-3g-hydroxy-8-fluoro 3,9,6,7,8,9-

hexahydro-isobenzofuran-l-one,

cis 5-phenyl-3-'8-chloro-3,9,6,7,8,9-hexahydroisobenzofuran-l-one,

cis 5-pheny1-3-8-dihydroXy-3,9,6,7,8,9-hexahydroisobenzofuran-l-one,

cis 5-phenyl-3z-hydroxy-8-trifluorornethyl-3,9,6,7,8,9-

hexahydro-isobenzofuran-l-one,

cis 5-phenyl-3.E-methyl-3g-hydroxy-8-benzyl-3,9,6,7,8,9-

hexahydro-isobenzofuran-l-one,

cis 5 (4-methoxyphenyl)-3.E-methyl-3-hydroxy-8-fluoro- 3,9,6,7,8,9-hexahydro-isobenzofuran-l-one,

cis 5-(4'-methoxyphenyl)-3g-methyl-3g-hydroxy-S-trichloromethyl-3,9,6,7,8,9'-hexahydro-isobenzofuran-lone,

cis 5-(4'-methoxyphenyl)-3-methyl-3g-hydroxy-8-trimethoxy-3,9,6,7,8,9-hexahydro-isobenzofuran-l-one,

cis S-(4'-methoxyphenyl)-3g-hydroxy-8-cyano-3,9,6,7,

8,9-hexahydro-isobenzofuran-1-one, and

cis 5-(4-methoxyheny1)-Sg-methyl-S.f-hydroxy-S-phenyl 3,9,6,7,8,9-hexahydro-isobenzofuran-1-one respectively.

By repeating the procedure of Example 21 using the above cis lactols as the starting material, there are obtained the cis keto esters, that is, the methyl ester of cis 4-phenyl-1-fluoro-2-acety1cyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-chloro-2-formylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-hydroxy-2-formylcyc1ohex-3-enecarboxylic acid,

cis 4-phenyl-l-trifluorornethyl-Z-formylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-l-benzyl-2-acetylcyclohex-3-enecarboxylic acid,

cis 4- (4'-methoxyphenyl l-fluoro-Z-acetylcyclohex-3- enecarboxylic acid,

cis 4-(4 methoxyphenyl)-l-trichloromethyl-Z-acetylcyciohex-3-enecarboxylic acid,

cis 4-(4'-methoxyphenyl)-1-methoxy-2-acetylcyclohex- 3-enecarboxylic acid,

cis 4- (4'-methoxyphenyl) -1-cyano-2-formylcyclohex-3- enecarboxylic acid, and

cis 4-(4'-methoxyphenyl)-l-phenyl-2-acetylcyclohex-3- enecarboxylic acid, respectively.

EXAMPLE 37 A mixture of 5 g. of the methyl ester of cis 4-phenyl- 1-fiuoro-2-acetylcyclohex-3-enecarboxylic acid in ml. of glacial acetic acid, 5 ml. of 1,2-eth'anedithiol, and 4 ml. of acetic acid, which has been previously saturated with anhydrous hydrogen chloride, is held at room temperature for four hours. The reaction mixture is then poured into water and extracted with several portions of ether. The organic phase is separated, dried and evaporated to dryness under reduced pressure to aiford the methyl ester of cis 4-phenyl-1-fluoro-2',2'-ethy]enedioxy-ethylcyclohex 3-enecarboxylic acid. A mixture of the thus-obtained intermediate and mg. of Raney nickel and 60 ml. of methanol, previously distilled over Raney nickel, is heated at reflux for 24 hours. The catalyst is removed by filtration, washed with methanol and the filtrate evaporated to dryness under reduced pressure. The residue is dissolved in chloroform. The chloroform solution is washed with dilute hydrochloric acid, aqueous 5% sodium carbonate solution and water, and then dried and evaporated to dryness to yield the methyl ester of cis 4-phenyl-1-fluoro- 2-ethylcyclohex-3-enecarboxylic acid which is subjected to the procedure of Example 28 to give cis 4-phenyl-1-fluoro- 2-ethylcyclohex-3-enecarboxylic acid.

By repeating the procedure of this example, other keto esters of the present invention, see Examples 21 and 36 for example, can be converted into the corresponding compounds, for example, the methyl ester of cis 4-phenyl-1-hydroxymethyl-2-ethylcyclohex-3-enecarboxylic acid,

cis 4-phenyll-fiuoro-Z-ethylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-chloro-2-methylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-l1ydroxy-2-methylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-trifiuoromethyl-2-methylcyclohex-3-enecarboxylic acid,

cis 4-phenyl-1-benzyl-2-ethylcyclohex-3-enecarboxylic acid,

cis 4-(4-methoxyphenyl)-1-fiuoro-2-ethylcyclohex-3- enecarboxylic acid,

cis 4- 4'-methoxyphenyl l -trichloromethyl-2-ethylcyclohex-3-enecarboxylic acid,

cis 4 (4'-methoxyphenyl l-methoxy-2-ethylcyclohex- 3-enecarboxylic acid,

cis 4- (4'-methoxypheny1 -1-cyano-2-methylcycl0hex-3 enecarboxylic acid, and

cis 4-(4-rnethoxyphenyl)-l-phenyl-2-ethylcyclohex-3- enecarboxylic acid,

respectively, and the corresponding free acids.

The above cyclohex-3-enecarboxylic acids and methyl esters thereof can be subjected to the procedures of Examples 24 and 25 to obtain the corresponding cyclohex-4- enecarboxylic acids and esters and cyclohexanecarboxylic acids and esters, e.g. cis 4-(-4-methoxyphenyl)-1-phenyl-2- ethylcyclohex-4-enecarboxylic acid and the methyl ester EXAMPLE 38 The procedure of Example 7 is repeated using cis 4-(4'- methoxyphenyl) 1 trichloromethyl-2-ethylcyclohexanecarboxylic acid as the starting material and there is obtained cis 4- (4'-hydroxyphenyl) l-trichloromethyl-Z-ethylcyclohexanecarboxylic acid. Using this procedure, other alkoxy substituted compounds of this invention can be converted into hydroxy substituted compounds.

EXAMPLE 39 A pyridine-sulfur trioxide adduct is prepared by the addition of 1 g. of liquid sulfur trioxide in 35 ml. of dry pyridine under a nitrogen atmosphere at about 10 C. to -5 C. To the adduct in pyridine is added 5 g. of cis 4- (4' hydroxyphenyl) 1 trichloromethyl-Z-ethylcyclohexanecarboxylic acid in 30 ml. of pyridine with continuous cooling. The reaction mixture is stirred for about 1.5 hours at C. and then for another two to three hours at room temperature. The reaction mixture is concentrated under reduced pressure. The concentrate is digested with dry ether until crystals form and then covered with dry ether and allowed to stand several hours. The reaction product is filtered and then dissolved in methanol and titrated with N sodium methylate to about pH 9. The mixture is filtered and the resulting filtrate concentrated under reduced pressure. The concentrated solution is cooled to about 40 C. to 50 C. and added to ether with stirring. The reaction product is filtered to give the disodium salt of cis 4-(4-hydroxyphenyl sulfate)-1-trichloromethyl-2-ethylcyclohexanecarboxylic acid.

The thus-obtained disodium salt is dissolved in methanol and poured onto a column containing the free acidform of an ion-exchange resin. The column is washed with methanol and the filtrate collected is evaporated to dryness under reduced perssure to give 4-(4'-hydroxyphenyl sulfate)-1-trichloromethyl-2-ethylcyclohexanecarboxylic acid.

EXAMPLE 40 A mixture of 2 g. of cis 4-(4'-hydroxyphenyl)-1-benzyl- 2-ethylcyclohex-4-enecarboxylic acid and 2 molar equivalents of fi-cyanoethyl phosphate in pyridine is combined with a pyridine solution of 8 molar equivalents of N,N'- dicyclohexylcarbodiimide and the reaction mixture is allowed to stand at room temperature for 24 hours. The reaction mixture is diluted with water (about 10 ml.) and allowed to stand at about C. for two days. The mixture is then evaporated to dryness under reduced pressure and the residue is taken up in about 35 ml. of aqueous methanol (1:1). This mixture is treated with about 12 mi. of 5% aqueous sodium hydroxide solution and after about one hour at room temperature it is concentrated under reduced pressure, diluted with 30 ml. of aqueous methanol, concentrated, and mixed with 75 ml. of water. This mixture is filtered and the filtrate is treated batchwise and then columnwise with an excess of sulfonic acid ionexchange resin (H form) to give cis 4-(4-hydroxyphenyl, '-dihydrogen phosphate)-l-benzyl-2-ethylcyclohex-4-enecarboxylic acid.

EXAMPLE 41 To a solution of 1 g. of cis 4- (4',6'-dimethoxyphenyl)- 1-fluoro-2,3-diethylcyclohex-3-enecarboxylic acid in 25 ml. of benzene, there is added with stirring a molar equivalent of potassium bicarbonate. This mixture is stirred until the evolution of carbon dioxide ceases and then the mixture is evaporated to afford the potassium salt of cis 4-(4,6- dimethoxyphenyl) 1 fluoro 2,3-diethylcyclohex-3-enecarboxylic acid.

By use of the above procedure, the other acids of the present inventionare converted into the potassium salt.

Similarly, by using sodium bicarbonate in the above pro- 24 cedure in place of potassium bicarbonate, the sodium salts are obtained.

Alternatively, acid salts can be prepared by titrating a solution of the free acid with an alcohol solution of an alkali metal alkoxide, e.g. potassium or sodium methoxide, to neutrality.

EXAMPLE 42 Instead of preparing the isothiouronium acetate of the compounds of Formula 5 above prior to the reaction with a tetronic acid to form the compounds of Formula HI, tetronic acid can be reacted directly with a compound of Formula 5 in the presence of an alkaline catalyst in an aromatic hydrocarbon solvent at elevated temperatures. For example:

To a solution of 1 g. of 4- (4'-cyclopentyloxyphenyl)-4- hydroxyhex-S-ene in 20 ml. of toluene is added 0.5 g. of triethylamine and 0.5 g. of u-fluoro-y-methyl tetronic acid. The resulting reaction mixture is heated at reflux in a nitrogen atmosphere for about four hours during which time the water of the reaction is removed. The reaction mixture is then partially concentrated by distillation, cooled and diluted with benzene. This mixture is washed with 5% aqueous potassium bicarbonate and water, dried over sodium sulfate and evaporated to dryness under reduced pressure to give inc-[3-(4'-cyclopentyloxyphenyl)- hex-2-enyl]-u'-fluoro-'y-methyl tetronic acid.

EXAMPLE 43 By repeating the procedure of Example 11 using a-[3- (4 methoxyphenyl) 5 methylhex 2 enyl] -o:.'-fll101'0- methyl-' -methyl tetronic acid and a-[3-(4'-methoxyphenyl) 5 methylhex 2 enyl] oc' chloromethyl-'y-methyl tetronic acid as the starting material, there is obtained 5 (4' methoxyphenyl) 4 isopropyl-S-fiuoromethyl-3- methyl-6,7,8,9-tetrahydro-isobenzofuran-l-one and 5-(4'- methoxyphenyl) 4 isopropyl 8-chloromethyl-3-methyl- 6,7,8,9-tetrahydro-isobenzofuran-l-one, respectively which are subjected to the procedures of Examples 17 and 23 to yield cis 4-(4'-methoxyphenyl)-l-fluoromethyl-Z-ethyl- 3-isopropylcyclohex-3-enecarboxylic acid and cis 4-(4'- methoxyphenyl) 1 chloromethyl 2 ethyl-S-isopropylcyclohex-3-enecarboxylic acid.

By using 5-(4'-methoxyphenyl)-4-isopropyl-8-difluoromethyl 3 methyl-6,7,8,9-tetrahydro-isobenzofuranl-one or 5-(4'-methoxyphenyl)-4-isopropyl-8-dichloromethyl-3- methyl 6,7,8,9 tetrahydro-isobenzofuran-l-one as the starting material in the process of Example 17, the corresponding cis lactols are obtained which are treated according to the procedure of Example 23 to give cis 4-(4'- methoxyphenyl 3 isopropyl l difluoromethyl-Z-ethylcyclohex-3-enecarboxylic acid and cis 4-(4'-methoxyphenyl) 3 isopropyl 1 dichloromethyl-2-ethy1cyclohex-3- enecarboxylic acid, respectively.

Alternatively, the above cis lactols can be first converted into the alkyl ester, e.g. methyl ester, using the procedure of Example 21, that is, the methyl ester of cis 4-(4-methoxyphenyl) 1 fluoromethyl-2-acetyl-3-isopropylcyclohex-3-enecarboxylic acid, methyl ester of cis 4- (4'-methoxyphenyl)-l-chloromethyl 2 acetyl-3-isopropylcyclohex-3-enecarboxylic acid, methyl ester of cis 4-(4'- methoxyphenyl)-l-difluorornethyl-Z-acetyl 3 isopropylcyclohex-S-enecarboxylic acid and methyl ester of cis 4- (4' methoxyphenyl)-l-dichloromethyl-3-isopropylcyclohex-3-enecarboxylic acid which can be subjected to the reduction procedure of either Example 23 or 37 to afford the methyl ester of cis 4-(4'-methoxyphenyl)-l-fluoromethyl-2-ethyl-3-isopropylcyclohex 3 enecarboxylic acid, cis 4-(4'-methoxyphenyl)-l-chloromethyl-2-ethyl-3- isopropylcyclohex-3-enecarboxylic acid, cis 4-(4-methoxyphenyl)l-difluoromethyl 2 ethyl-3-isopropylcyclohex- 3-enecarboxylic acid, and cis-4-(4-methoxyphenyl)-l-dichloromethyl-2-ethyl-3-isopropylcyclohex 3 enecarboxylic acid, respectively. The thus-obtained methyl esters can be converted into the corresponding free acids using the procedure of Example 28.

25 What is claimed is: 1. A compound selected from those of the formula:

wherein,

R is chloro, fluoro, chloromethyl, fluoromethyl, dichloromethyl, difiuoromethyl, trichloromethyl, or trifluoromethyl;

R is methyl or ethyl;

R is hydrogen, methyl, ethyl, or isopropyl;

R is lower alkoxy, cyclopentyloxy, cyclohexyloxy, tet rahydropyran-2yloxy, or tetrahydrofuran-2-yloxy;

R is lower alkyl or hydrogen;

R is the group COOR in which R is hydrogen, an

alkali metal or lower alkyl; and

each of Z and Z is a carbon to carbon single bond or double bond, provided that at least one of Z and Z is a single bond.

2. A compound according to claim 1 wherein R is methoxy, R is hydrogen and R is the group COOR.

3. A compound according to claim 1 wherein R is chloromethyl, fiuoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, or trifiuoromethyl.

4. A compound according to claim 1 wherein R is fluoro, chloromethyl, fiuoromethyl, dichloromethyl, difiuoromethyl, trichloromethyl or trifiuoromethyl and R is the group COOR in which R is hydrogen or lower alkyl.

5. A compound according to claim 4 wherein R is methoxy and R is hydrogen.

6. A compound according to claim 3 wherein R is difluoromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

7. A compound according to claim 1 wherein R is fluoro, R is ethyl, R is hydrogen, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

8. A compound according to claim 1 wherein R is trichloromethyl, R is ethyl, R is hydrogen, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z isa carbon-carbon single bond and Z' is a carbon-carbon double bond.

9. A compound according to claim 1 wherein R is fiuoromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z is a carbon-carbon single bond and Z' is a carbon-carbon double bond.

10. A compound according to claim 1 wherein R is chloromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z is a carbon-carbon single bond and Z' is a carbon-carbon double bond.

11. A compound according to claim 1 wherein R is dichloromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is hydrogen, Z is a carbon-carbon single bond and Z' is a carbon-carbon double bond.

12. A compound according to claim 1 wherein R is fiuoromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is methyl, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

13. A compound according to claim 1 wherein R is chloromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is methyl, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

14. A compound according to claim 1 wherein R is difiuoromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is methyl, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

15. A compound according to claim 1 wherein R is dichloromethyl, R is ethyl, R is isopropyl, R is methoxy, R is hydrogen, R is the group COOR in which R is methyl, Z is a carbon-carbon single bond and Z is a carbon-carbon double bond.

OTHER REFERENCES Yale. J. of Medicinal & Pharmaceutical Chemistry, vol. No. 2, p. 121 (1959).

LORRAINE A. WEINBERGER, Primary Examiner J. F. TERAPANE, Assistant Examiner US. Cl. X.R.

260-29367, 293.72, 293.78, 293.8, 293.81, 293.82, 340.9, 343.3, 343.6, 345.7, 345.8, 345.9, 347.3, 347.4, 347.8, 410.5, 458, 465 D, 465 F, 465 G, 465 K, 468 R, 468 F, 469, 471 R, 473 R, 473 A, 476 R, 479 R, 482 R, 484 R, 485 L, 486 R, 487, 488 CD, 501.19, 501.21, 515 R, 515 A, 520, 544 M, 544 F, 558 R, 559 R, 559 B, 592, 599, 600, 611 A, 612 R, 613 R, 613 D, 618 R, 621 K, 930', 940, 941, 942, 943, 944, 946, 951, 952, 953, 955; 424--206, 210, 211, 212, 214, 267, 283, 285, 303, 304, 308, 311, 315, 317, 324, 333, 339, 340, 341, 343 

